Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease

Background: The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown. Objective: Our objective was to assess exposure to morphine as an etiologic factor for acute chest syndrome in sickle cell disease. Methods: A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5-17 years) with sickle cell crisis were randomized to receive oral sustained-release morphine, 1.9 mg·kg^-1·12 h^-1, or a continuous intravenous infusion of morphine at 0.04 mg·kg^-1·h^-1 by use of a double-blind, placebo-controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide were also studied. Results: At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2-fold higher morphine area under the concentration-time curve at steady state (AUC_ss) and a 3-fold higher morphine-6-glucuronide AUC _ss with oral morphine than with a continuous intravenous infusion of morphine (P < .001 and P < .006, respectively). New onset of acute chest syndrome was 3-fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (P < .001). Conclusions: The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine-6-glucuronide after oral administration of slow-release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as-yet-unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration-time curve should be further studied in children with sickle cell disease.